• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
* * * * * 3 votes

Functioning of aged brains in mice made younger: More progress with GDF 11, anti-aging protein

gdf-11 brain function

  • Please log in to reply
17 replies to this topic

#1 LexLux

  • Guest
  • 265 posts
  • 88
  • Location:London, UK
  • NO

Posted 12 May 2014 - 05:38 PM


 Anyone have any idea what foods or supps could up-regulate the GDF-11 protein?

 

"Scientists have shown that a protein they previously demonstrated can make the failing hearts in aging mice appear more like those of young health mice, similarly improves brain and skeletal muscle function in aging mice. In two separate articles scientists report that injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human."

 
[...]
 

"In two separate papers given early online release today by the journal Science, which is publishing the papers this coming Friday, Professors Amy Wagers and Lee Rubin, of Harvard's Department of Stem Cell and Regenerative Biology (HSCRB), report that injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human, and also improved the function of the olfactory region of the brains of the older mice -- they could detect smell as younger mice do.

Rubin and Wagers each said that, baring unexpected developments, they expect to have GDF11 in initial human clinical trials within three to five years. Postdoctoral fellow Lida Katsimpardi is the lead author on the Rubin group's paper, and postdocs Manisha Sinha and Young Jang are the lead authors on the paper from the Wagers group.

Both studies examined the effect of GDF11 in two ways. First, by using what is called a parabiotic system, in which two mice are surgically joined and the blood of the younger mouse circulates through the older mouse. And second, by injecting the older mice with GDF11, which in an earlier study by Wagers and Richard Lee, of Brigham and Women's Hospital who is also an author on the two papers released today, was shown to be sufficient to reverse characteristics of aging in the heart."

 

[...]

 

""We think an effect of GDF 11 is the improved vascularity and blood flow, associated with increased neurogenesis," Rubin said. "This should have other more widespread effect on other areas of the brain. We do think that, at least in principal, there will be a way to reverse some of the decline of aging with a single protein. It could be that a molecule like GDF 11, or GDF 11 itself, could" reverse the damage of aging."

 

[...]

 

""It isn't out of question that GDF11," or a drug developed from it, "might be capable of slowing some of the cognitive defects associated with Alzheimer's Disease, a disorder whose main risk factor is aging itself," Rubin said. It is even possible that this could occur without directly changing the "plaque and tangle burden" that are the pathological hallmarks of Alzheimer's. Thus, a future treatment for this disease might be a combination of a therapeutic that reduces plaques and tangles, such as an antibody directed against the ?-amyloid peptide, with a potential cognition enhancer like GDF-11."

 

-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Harvard University. "Functioning of aged brains and muscles in mice made younger: More progress with GDF 11, anti-aging protein." ScienceDaily. ScienceDaily, 4 May 2014. <www.sciencedaily.com/releases/2014/05/140504133205.htm>.

 


  • like x 4

#2 LexLux

  • Topic Starter
  • Guest
  • 265 posts
  • 88
  • Location:London, UK
  • NO

Posted 12 May 2014 - 05:42 PM

Activation of the growth-differentiation factor 11 gene by the histone deacetylase (HDAC) inhibitor trichostatin A and repression by HDAC3.

[click hyperlink for full text]
Abstract

Histone deacetylase (HDAC) inhibitors inhibit the proliferation of transformed cells in vitro, restrain tumor growth in animals, and are currently being actively exploited as potential anticancer agents. To identify gene targets of the HDAC inhibitor trichostatin A (TSA), we compared the gene expression profiles of BALB/c-3T3 cells treated with or without TSA. Our results show that TSA up-regulates the expression of the gene encoding growth-differentiation factor 11 (Gdf11), a transforming growth factor beta family member that inhibits cell proliferation. Detailed analyses indicated that TSA activates the gdf11 promoter through a conserved CCAAT box element. A comprehensive survey of human HDACs revealed that HDAC3 is necessary and sufficient for the repression of gdf11 promoter activity. Chromatin immunoprecipitation assays showed that treatment of cells with TSA or silencing of HDAC3 expression by small interfering RNA causes the hyperacetylation of Lys-9 in histone H3 on the gdf11 promoter. Together, our results provide a new model in which HDAC inhibitors reverse abnormal cell growth by inactivation of HDAC3, which in turn leads to the derepression of gdf11 expression.

[...]

 

"To determine whether TSA increases amounts of Gdf11 mRNA in human cells, Northern blot assays were done using RNA prepared from TSA-treated and untreated HeLa cells. Similar to the response in BALB/c-3T3 cells, Gdf11 mRNA was much more abundant in TSA-treated than in untreated HeLa cells (Fig. ​(Fig.1C).1C). However, Gdf11 induction in HeLa cells required a much greater concentration of TSA than did Gdf11 induction in BALB/c-3T3 cells. Similar to HeLa cells, TSA also induced Gdf11 mRNA expression in a normal diploid fibroblast cell line, Flow 2000, although to a lesser extent.

 

To determine whether increases in the abundance of Gdf11 mRNA result in increases in the abundance of Gdf11 protein, we generated a polyclonal anti-Gdf11 antibody and performed a Western blot assay using protein extracts prepared from HeLa cells treated or untreated with TSA. As shown in Fig. ​Fig.1D,1D, TSA clearly increased the amount of Gdf11 protein in HeLa cells."

 

 

Supplements like sodium butyrate and prebiotics like RS and FOS also seem interesting. For sodium butyrate, you can see it go up against drugs like trichostatin A and valproic acid here:

 

http://www.ncbi.nlm....9941/figure/F4/

http://www.ncbi.nlm....9941/figure/F3/

 

The last two citations look at "GDNF" not "GDF-11", but since both are influenced by H3 acetylation, this gives an interesting comparison of the effectiveness of various HDAC inhibitors. Sodium butyrate seems to hold up surprisingly well. 
 
 

 


Edited by LexLux, 12 May 2014 - 06:30 PM.

  • like x 2

sponsored ad

  • Advert
Click HERE to rent this advertising spot for BRAIN HEALTH to support LongeCity (this will replace the google ad above).

#3 LexLux

  • Topic Starter
  • Guest
  • 265 posts
  • 88
  • Location:London, UK
  • NO

Posted 12 May 2014 - 07:35 PM

Na Butyrate also seems promising for cancer : http://europepmc.org...hBaWIANGrOQH.24

 

 

Anyone know anything about the effective dosage for Na Butyrate and how oral supplementation compares to production of butyrate via fermentation of prebiotics like FOS and RS in the colon? 

 

http://www.direct-ms...olon cancer.pdf

http://onlinelibrary...003.01836.x/pdf

 

As pointed out by Celebes in this thread, Na Butyrate was "the only other HDAC inhibitor shown to facilitate complete fear extinction (apart from vorinostat and valproate):

 

http://www.ncbi.nlm....port=objectonly"

 


Edited by LexLux, 12 May 2014 - 07:59 PM.

  • like x 4
  • dislike x 1

#4 LexLux

  • Topic Starter
  • Guest
  • 265 posts
  • 88
  • Location:London, UK
  • NO

Posted 12 May 2014 - 08:33 PM

Na Butyrate just seems a lot cheaper than the safe HDAC inhibiting drugs and is an endogenous compound. Vorinostat is really expensive and comes with some side effects.


Edited by LexLux, 12 May 2014 - 09:10 PM.

  • like x 1

#5 Phoenicis

  • Guest
  • 339 posts
  • 79
  • Location:-
  • NO

Posted 13 May 2014 - 06:42 AM

Here are some HDACis in clinical trials, I am curious about clinical trials involving trichostatin A but it seems that this natural product was developed further into vorinostat and I'm not sure if it underwent trials itself? 

 

Ioannis Koutsounas, Constantinos Giaginis, and Stamatios Theocharis

 

"Hydroxamic acids
SAHA (N-hydroxy-N’-phenyl-octanediamide, vorinostat) is a synthetic hydroxamic acid, which is structurally related to the natural product, [trichostatin A] TSA (7-[4-(dimethylamino)phenyl]-N-hydroxyl-4,6-dimethyl-7-oxo-(2E,4E,6R)-2,4-heptadienamide), produced by selected strains of Streptomyces platensis, Streptomyces hygroscopicus Y-50 or Streptomyces sioyaensis. Hydroxamic acids have a high affinity to biometals, including Fe3+, Ni2+ and Zn2+. The synthesis of SAHA and its potency to induce differentiation of murine erythroleukemia (MEL) cells was first reported in 1996. SAHA and TSA comprise a hydroxamic-acid-based metal-binding domain that coordinates the catalytic Zn2 +in the HDAC active site, a 5 (TSA) or 6 (SAHA)-membered carbon-based linker that mimics the Cα functional group of lysine, and a hydrophobic motif that interacts with the periphery of the HDAC binding pocket[28].
 
SAHA:SAHA (vorinostat) is now undergoing several clinical trials. One current phase I  trial is studying the side effects and best dose of SAHA given together with flavopiridol in treating patients with advanced solid tumors. Another trial is studying SAHA in patients with metastatic or unresectable solid tumors or lymphoma and liver dysfunction. Combination with doxorubicin is also under survey for solid tumors, as well as that with bortezomib, vinorelbine, gemcitabine and other agents like paclitaxel and carboplatin, fluorouracil/leucovorin and oxaliplatin. A phase I /II trial is studying the highest tolerable dose of SAHA that can be given in combination with radiotherapy to patients with locally advanced pancreatic cancer, as well the efficacy of combined therapy. Another phase I  clinical trial is now examining the safety, pharmacokinetics, pharmacodynamics and efficacy of iv proteasome inhibitor NPI-0052 in combination with oral SAHA in patients with non-small cell lung cancer, pancreatic cancer, melanoma or lymphoma. A phase I /II study of SAHA in combination with radiotherapy and infusional 5-FU in patients with locally advanced adenocarcinoma of the pancreas is under way. Finally, SAHA in combination with capecitabine plus radiotherapy is also being evaluated in patients with non-metastatic pancreatic cancer. The above studies are recruiting for participants and possible patients suffering from pancreatic cancer remain to determine the efficiency of these therapies[29].
 
Cyclic peptides
FK228 (FR901228, depsipeptide, romidepsin): Depsipeptide (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis (1-methyletheyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone, is a bicyclic peptide isolated from Chromobacterium violaceum and has demonstrated potent in vitro cytotoxic activity against human tumor cell lines and in vivo efficacy against human tumor xenografts. Upon entering cells, FK228 is reduced to an active compound, capable of preferentially interacting with the zinc in the active site of the HDAC class I enzymes, however, it is still generally classified as a broad-spectrum inhibitor as it does inhibit class II enzymes. It was approved by the United States Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL)[30].
 
Among other current clinical trials for patients with advanced solid tumors, FK228 is being studied in combination with gemcitabine in patients with pancreatic cancer. This phase I/II dose escalation trial is designed to determine the maximum tolerated dose for the combination, as well as evaluate toxicities and objective disease responses. Furthermore, another phase II trial is studying the effectiveness of FK228 in patients who have locally advanced or metastatic neuroendocrine tumors; among them pancreatic islet tumors[29].
 
Short-chain fatty acids
Valproic acid: Valproic acid (VPA) is now an established antiepileptic drug, by affecting the function of the neurotransmitter GABA. The finding that VPA was an effective inhibitor of HDACs arose from the observations that VPA was able to relieve transcriptional repression of a peroxisomal proliferation and activation of a glucocorticoid receptor (GR)-PPAR epsilon hybrid receptor, suggesting that it acts on a common mechanism in gene regulation, such as histone deacetylation, rather than on individual transcription factors or receptors. Consistent with this finding, it was shown that VPA causes hyperacetylation of the N-terminal tails of histones H3 and H4 in vitro and in vivo, and was found to inhibit HDAC enzymatic activity at a concentration of 0.5 mmol/L[31]. VPA has shown potent antitumor effects in a variety of in vitro and in vivo systems, by modulating multiple pathways including cell cycle arrest, apoptosis, angiogenesis, metastasis, differentiation and senescence. Most preclinical and clinical data on the anticancer effects of VPA have been generated for malignant hematological diseases[32].
 
A phase I clinical trial investigated the safety, toxicity and maximum-tolerated dose of VPA and the topoisomerase II inhibitor epirubicin in solid tumors. Forty-eight patients with different malignancies were enrolled; one with pancreatic cancer. The patient suffering from pancreatic cancer experienced a partial response at 100 mg/kg VPA and 100 mg/m2 on day 3 of the cycle, while no dose-limiting toxicities occurred. All patients with a partial response had at least a twofold increase in histone acetylation[33].
 
Phase I clinical trials are currently testing VPA in combination with other agents such as erlotinib, 5-FU, cyclophosphamide, bevacizumab, and azacytidine, as well as epirubicin to determine safety, tolerability and effectiveness in treating patients with advanced solid tumors. In addition, another phase II trial is studying VPA combined with the hypomethylating factor hydralazine. A phase I clinical trial is undertaking recruitment to determine maximum tolerated doses of VPA in combination with sunitinib, sorafenib, dasatinib, erlotinib, lapatinib, or lenalidomide for the treatment of patients with advanced solid tumors, as well as to estimate the safety and treatment response[29].
 
4-PB:
4-PB is a short-chain fatty acid known to inhibit reversibly class I and II HDACs. It is considered as an HDAC inhibitor of the first generation, as the HDAC inhibitory effect is not specific. Working concentrations are rather high, in the millimolar range, and the effects are pleiotropic. 4-PB is known to exert multiple effects in the cell, including the modulation of protein isoprenylation, which importantly regulates the ras proto-oncoprotein, and activation of the nuclear steroid PPAR[34]. 4-PB exerts a potent antitumor effect in vitro and has been shown to cause growth inhibition and differentiation in various human cancer cell lines[35].
 
A phase I dose escalating trial to evaluate twice daily iv 4-PB infusion has been undertaken. 4-PB was administered for five consecutive days for a total of 20 doses over two consecutive weeks from 60 to 360 mg/kg per day. Twenty-one patients with different malignancies, including one with pancreatic carcinoma, participated in the trial. Dose limiting toxicities were fatigue and headache, while no significant myelosuppression was seen. Three patients with brain malignancies remained stable for an average of 6 mo[36].
 
A current phase I clinical trial is investigating oral phenylbutyrate three times daily in patients with refractory solid tumors. Combination with azacytidine is also being studied to determine effectiveness and maximum dose in patients with advanced or metastatic solid tumors[29].
 
NaBu:
NaBu has multiple effects on cultured mammalian cells that include inhibition of proliferation, induction of differentiation and induction or repression of gene expression. Sodium butyrate inhibits most HDACs except class III HDAC and class II HDAC6 and-10. Promoters of butyrate-responsive genes have butyrate response elements, and the action of butyrate is often mediated through Sp1/Sp3 binding sites[37].
 
In a recruiting phase I clinical trial, the butyrate prodrug tributyrin is being studied in patients with various advanced solid tumors[29].
 
Benzamides
MS-275: This synthetic benzamide derivative (3-pyridylmethyl-N-{4-[(2-aminophenyl)carbamoyl]benzyl}carbamate) has been shown to inhibit HDACs, and has antitumor activity in many preclinical models. The first clinical trial with this agent in 2005 included patients with advanced solid tumors or lymphoma. At high concentrations of MS-275, there is a marked induction of reactive oxygen species, mitochondrial damage, caspase activation and apoptosis. Treatment of sensitive tumor cell lines with MS-275 induces gelsolin, a maturation marker, and produces a change in the cell cycle distribution with a decrease in S phase and an accumulation of cells in G1. The in vivo therapeutic efficacy of MS-275 has been shown in a variety of human tumor xenograft models[38].
 
A phase I study determined the maximum tolerated dose, the dose limiting toxicity and the pharmacokinetic or pharmacodynamic profile of MS-275 in combination with 13-cis-retinoic acid. Patients with advanced solid tumors were treated with MS-275 orally, once weekly, and 13-cis-retinoic acid orally, 1 mg/kg twice daily, for 3 wk every 4 wk. One patient suffering from pancreatic cancer remained on treatment for 6 mo and a patient with renal cell carcinoma showed a partial response in the lungs. Side effects included hyponatremia, neutropenia, anemia and fatigue[39].
 
Another phase I study evaluated the toxicity and pharmacokinetic profiles of MS-275 in patients with refractory solid tumors and lymphomas, including one patient suffering from metastatic pancreatic cancer, on three different schedules. The patient with metastatic pancreatic cancer developed grade 3 hypophosphatemia, thus meeting criteria for dose limiting toxicity, and was finally removed from study due to disease progression after cycle 2. Objective responses were only observed in patients receiving the every-other-week dosing schedule, but the numbers of patients enrolled were too small to determine whether this dosing regimen was truly more efficacious[40].
 
CI-994:
CI-994 or N-acetyldinaline [4-(acetylamino)-N-(2-amino-phenyl) benzamide] is a novel oral compound with a wide spectrum of antitumor activity in preclinical models. The mechanism of action may involve inhibition of histone deacetylation and cell cycle arrest. CI-994 is currently undergoing clinical trials. Although several changes in cellular metabolism induced by the drug have been characterized, the primary molecular mechanism of its antitumor activity remains unknown[41].
 
A phase II trial of CI-994 in patients with advanced pancreatic cancer evaluated the antitumor activity and safety of CI-994. CI-994 was administered orally at 8 mg/m2 per day. Seventeen patients were enrolled, including 15 with metastatic disease. Among patients evaluable for response, stable disease for 8 wk occurred in two patients (12%). Overall, median time to progressive disease was 6 wk and median survival was 10 wk, with one patient alive at 41 wk. Grade 3 thrombocytopenia occurred in eight patients but grade 4 in none. Most common non-hematological toxicities were generally grade 1 or 2 and included fatigue, anorexia, nausea, vomiting and bruising. According to this study, CI-994 was well tolerated but resulted in no objective responses in patients with advanced pancreatic cancer[42].
 
A phase 1 study in patients with solid tumors was carried out to determine the maximum tolerated daily oral dose for CI-994 administered on a chronic basis. Fifty-three patients, most of them suffering from colorectal, lung and renal malignancies, including one with pancreatic cancer, received CI-994 daily for treatment durations ranging from 2 to 10 wk. Antitumor effects were documented in four patients, including a durable partial response in one pretreated non-small cell lung cancer patient and stable disease in three patients with non-small cell lung, colon and renal cancers[43].
 
Another study investigated the toxicity profile, maximum tolerated dose and pharmacokinetics of CI-994 in combination with capecitabine. Fifty-four patients were treated according to three different dosing schemes in which the capecitabine dose was fixed and the CI-994 dose was escalated. In schedule C, 22 patients, including four with pancreatic cancer, were treated with capecitabine 2000 mg/m2 per day and CI-994 for 2 of 3 wk. One partial response was achieved at the 4 mg/m2 dose level of schedule A in a patient with colorectal cancer. Disease stabilization was seen in adenocarcinoma of unknown primary origin, appendiceal cancer, breast cancer, colorectal cancer and mesothelioma[44].
 
A phase I study of oral CI-994 in combination with carboplatin and paclitaxel in patients with advanced solid tumors was carried out. A total of 30 patients were entered into five treatment cohorts, including two suffering from pancreatic cancer. Five patients achieved a partial response (non-small cell lung, colon, unknown primary origin) and two patients achieved a complete response (esophageal and bladder cancer). It was observed that patients whose histone H3 acetylation in peripheral blood lymphocytes was at least 1.5-fold greater after treatment had an objective clinical response or stable disease[45].
 
A randomized, double-blind, placebo-controlled, multicenter study compared whether CI-994 plus gemcitabine improved OS, duration of response, time to treatment failure, and quality of life compared to gemcitabine alone. Patients had diagnosis of advanced or metastatic adenocarcinoma of the exocrine pancreas and were not considered surgical candidates. A total of 174 patients received CI-994 6 mg/m2 per d orally on days 1-21 plus gemcitabine 1000 mg/m2 on days 1, 8 and 15 or placebo plus gemcitabine 1000 mg/m2 on days 1, 8 and 15 of each 28-d cycle. There was no observed difference in survival time between the two cases. The estimated median survival was 194 and 214 d and objective response rates based on investigator assessments were 12% and 14%, respectively. In addition, pain responses did not differ significantly. Treatment with CI-994 was associated with more cases of grade 3/4 thrombocytopenia, anemia and leukopenia than with placebo, while non-hematological toxicities such as nausea, vomiting, anorexia and diarrhea were identical with both treatments. Consequently, in this study, CI-994 in combination with gemcitabine did not appear to offer any benefit compared to gemcitabine as a single agent for the treatment of pancreatic cancer[46].
 
A randomized phase II trial comparing the effectiveness of gemcitabine with or without CI-994 in patients with advanced pancreatic cancer is still ongoing[29].
 
MGCD0103:
MGCD0103 is an isotype-specific aminophenylbenzamide that inhibits HDAC classes I and IV, with almost no class II effect. MGCD0103 is well tolerated and exhibits favorable pharmacokinetic and pharmacodynamic profiles, demonstrating target inhibition and clinical responses. It induces cell death and autophagy, synergizes with proteasomal inhibitors and affects non-histone targets, such as microtubules[47].
 
In a phase I study MGCD0103 was given three times weekly orally to patients with advanced solid tumors to determine safety, tolerability and pharmacokinetics. Thirty-eight patients were enrolled and completed a total of 99 cycles of MGCD0103, including two with pancreatic cancer. No objective tumor responses were observed. Five patients with previously progressive colorectal, renal cell and lung cancers had stable disease for four or more cycles. Furthermore, MGCD0103 exerted dose-dependent HDAC inhibitory activity and was able to induce histone acetylation in peripheral leukocytes[48].
 
Oral MGCD0103 three times weekly is currently being studied in combination with gemcitabine, in patients with advanced solid tumors. In this phase I/II study, patients with locally advanced or metastatic pancreatic cancer can participate. Maximum tolerated dose of MGCD0103 and objective response of patients remain to be determined[29,49].
 
Other HDACIs
A phase I study of LAQ824 has determined the safety, maximum tolerated dose, and pharmacokinetic-pharmacodynamic profile in patients with advanced solid tumors. Thirty-nine patients were recruited and were eligible for assessment of toxicity, including three with pancreatic cancer. At 100 mg/m2, one patient who had advanced pancreatic cancer, developed grade 4 hyperbilirubinemia associated with febrile neutropenia on day 3. The patient finally died after an episode of atrial fibrillation and acute renal failure 18 d after the first infusion. All patients treated with LAQ824 at 12 mg/m2 or above showed increase in histone acetylation. No objective responses were documented. One patient with hepatocellular carcinoma and two with fibrosarcoma and papillary carcinoma of the thyroid showed disease stabilization[50].
 
A phase I study is investigating safety, pharmacodynamic, antitumor activity, and pharmacokinetics of PXD101 (belinostat) alone and in combination with 5-FU in patients with advanced solid tumors or lymphoma[51]. Another recruiting phase I trial is studying the safety, tolerability and pharmacokinetics of orally administered PXD101 in combination with carboplatin and/or paclitaxel in patients with advanced solid tumors or lymphoma[52].
 
A recruiting phase I study is evaluating the pharmacokinetics and safety of oral LBH589 (panobinostat) in patients with advanced solid tumors and varying degrees of renal function. Another phase II trial will determine tumor response, toxicity and tolerability of LBH589 in patients with gastrointestinal neuroendocrine tumors. A phase IA, dose-escalating study of iv LBH589 in adult patients with advanced solid tumors is ongoing. Another phase I study will evaluate the safety and tolerability of the combination of LBH589 and paclitaxel/carboplatin in patients with metastatic or locally advanced solid tumors. Finally, a phase I dose escalation trial of LBH589 and gemcitabine in patients with solid malignancies has been temporarily suspended[53,54].
 
Other HDACIs, such as CHR-3996, CRA-024781, SB939 and R306465, are under phase I trials for the treatment of patients with advanced solid tumors[29]."

Edited by Phoenicis, 13 May 2014 - 06:47 AM.


#6 LexLux

  • Topic Starter
  • Guest
  • 265 posts
  • 88
  • Location:London, UK
  • NO

Posted 13 May 2014 - 04:58 PM

A source has just let know that he thinks using any of these HDAC inhibitors for the purpose of up-regulating GDf-11 is not advisable, as they are not specific just to GDF-11. More testing on their long term safety is necessary and as always, I'm discussing this topic out of academic interest and I am not advising anyone to take these. I am not a doctor, or even and expert, so seek independent medical advice before supplementing anything discussed here. 


Edited by LexLux, 13 May 2014 - 05:58 PM.

  • like x 1

#7 Phoenicis

  • Guest
  • 339 posts
  • 79
  • Location:-
  • NO

Posted 14 May 2014 - 01:06 AM

While I agree that no one should go running off taking any of these compounds without seeking independent medical advice from a doctor, I just want to bring something up for discussion purposes. 

 

What I want to discuss is butyrate and its prodrug tributyrin - people have noted how quickly butyrate is metabolised, but it seems tributyrin has much better pharmokinetics and the other interesting thing is that tributyrate is sold as a food grade flavor?!  10kg for 200 British pounds? Am I mistaken? Apparently it's naturally present in butter as well.

 

Tributyrin, a Stable and Rapidly Absorbed Prodrug of Butyric Acid, Enhances Antiproliferative Effects of Dihydroxycholecalciferol in Human Colon Cancer Cells

 

 Tanja Gaschott, Dieter Steinhilber*, Vladan Milovic, and Jürgen Stein2

 

"Butyrate, a normal constituent of the colonic luminal contents, is formed by bacterial fermentation of unabsorbed complex carbohydrates in the mammalian digestive tract. In normal colonic mucosa, butyrate serves as a primary energy source, promotes growth of normal colonic epithelial cells in vivo and in vitro and plays a role in preventing certain types of colitis (1). In contrast, in a wide variety of neoplastic cells, butyrate acts as a potent antineoplastic agent, i.e., it inhibits growth and induces differentiation, restoring normal phenotype and function (2). The studies done during the last decade provide multiple lines of evidence that butyrate indeed interferes with the pathogenesis of colorectal cancer. Butyrate inhibits DNA synthesis and arrests growth of neoplastic colonocytes in G1 (3), modifies expression of genes involved in chemotherapy resistance (4) and in cell proliferation/differentiation (5, ,6), and induces apoptosis by a p53-independent pathway (7). At least some of butyrate’s antineoplastic effects in colon cancer cells may be due to its synergistic action with another antiproliferative agent, 1,25-dihydroxyvitamin D3 [dihydroxycholecalciferol; (OH)2D3]. In various cancer cell lines it has been shown that butyrate and (OH)2D3 act synergistically in reducing proliferation and enhancing differentiation of neoplastic cells (8, 9, 10).

 

In spite of its early promise, butyrate is not among the drugs used for cancer treatment. The major problem has been to achieve and maintain its millimolar concentrations in blood. Butyrate is metabolized rapidly as soon as it enters the colonocyte via its active transport system (11, 12, 13), and its plasma concentrations are far below those required to exert its antiproliferative/differentiating actions.

 

A prodrug of natural butyrate, tributyrin, is a neutral short-chain fatty acid triglyceride that is likely to overcome the pharmacokinetic drawbacks of natural butyrate as a drug (14). Because it is rapidly absorbed and chemically stable in plasma, tributyrin diffuses through biological membranes and is metabolized by intracellular lipases, releasing therapeutically effective butyrate over time directly into the cell. Compared with butyrate, tributyrin has more favorable pharmacokinetics (141516) and is well tolerated (17). Liquid tributyrin filled into gelatin capsules and administered orally resulted in millimolar concentrations of butyrate both in plasma and inside the cell (17). In vitro, tributyrin has potent antiproliferative, proapoptotic and differentiation-inducing effects in neoplastic cells (181920). In this study, human colon cancer cells (Caco-2) were used to investigate the effects of tributyrin on growth and differentiation."

 

 

CLINICAL TRIALS -

 

1) Phase I study of the orally administered butyrate prodrug, tributyrin, in patients with solid tumors.

 

Butyrates have been studied as cancer differentiation agents in vitro and as a treatment for hemoglobinopathies. Tributyrin, a triglyceride with butyrate molecules esterified at the 1, 2, and 3 positions, induces differentiation and/or growth inhibition of a number of cell lines in vitro. When given p.o. to rodents, tributyrin produces substantial plasma butyrate concentrations. We treated 13 patients with escalating doses of tributyrin from 50 to 400 mg/kg/day. Doses were administered p.o. after an overnight fast, once daily for 3 weeks, followed by a 1-week rest. Intrapatient dose escalation occurred after two courses without toxicity greater than grade 2. The time course of butyrate in plasma was assessed on days 1 and 15 and after any dose escalation. Grade 3 toxicities consisted of nausea, vomiting, and myalgia. Grades 1 and 2 toxicities included diarrhea, headache, abdominal cramping, nausea, anemia, constipation, azotemia, lightheadedness, fatigue, rash, alopecia, odor, dysphoria, and clumsiness. There was no consistent increase in hemoglobin F with tributyrin treatment. Peak plasma butyrate concentrations occurred between 0.25 and 3 h after dose, increased with dose, and ranged from 0 to 0.45 mM. Peak concentrations did not increase in three patients who had dose escalation. Butyrate pharmacokinetics were not different on days 1 and 15. Because peak plasma concentrations near those effective in vitro (0.5-1 mM) were achieved, but butyrate disappeared from plasma by 5 h after dose, we are now pursuing dose escalation with dosing three times daily, beginning at a dose of 450 mg/kg/day.

 

2) Clinical and pharmacologic study of tributyrin: an oral butyrate prodrug

 

 

Purpose

Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50–100 μM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 μM. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule.

 

Patients and methods

Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 h thereafter.

 

Results

The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30–74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 μM was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression.

 

Conclusion

Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing.

 

3) No results posted here? http://www.clinicalt...ibutyrin&rank=1


Edited by Phoenicis, 14 May 2014 - 01:10 AM.


#8 Flex

  • Guest
  • 1,629 posts
  • 149
  • Location:EU

Posted 14 May 2014 - 07:25 AM

Nice findings.

 

Is there any possibility to decrease the metabolism of Sodiumbutyrate ?

However, I´ve learned recently that Hdac inhibition can be even harmful

HDAC inhibitors: roles of DNA damage and repair.

http://www.ncbi.nlm....pubmed/23088869

 

Just Btw, if someone is interrested:

Effects of sodium butyrate on the expression of sodium channels by neuronal cell lines derived from the rat CNS

http://www.ncbi.nlm..../pubmed/1283997

 



#9 Phoenicis

  • Guest
  • 339 posts
  • 79
  • Location:-
  • NO

Posted 14 May 2014 - 03:44 PM

Thanks to the studies bellow, the hypothesized mechanism of action for tributyrin seems to be: 

 

Tributyrin -> therapeutic levels of Na butyrate in vivo -> HDAC 3 inhibition -> increased GDF 11 expression

 

Activation of the Growth-Differentiation Factor 11 Gene by the Histone Deacetylase (HDAC) Inhibitor Trichostatin A and Repression by HDAC3  Xiaohong Zhang, Walker Wharton, [...], and Edward Seto

 

"Together, our results provide a new model in which HDAC inhibitors reverse abnormal cell growth by inactivation of HDAC3, which in turn leads to the derepression of gdf11 expression."

[...]

"...To confirm that HDAC3 is involved in the repression of the gdf11 promoter, we used a DNA vector-based RNA interference (RNAi) method to suppress HDAC3 expression in HeLa cells. small interfering RNAs (siRNAs) targeting HDACs 1, 2, and 3 synthesized from the BS/U6 template efficiently inhibited the expression of HDAC1, -2, and -3, respectively, but not of the control protein β-actin, as monitored by immunoblotting (Fig. ​(Fig.4C).4C). Transfection with the BS/U6 vector (control) had no effect on the abundance of any of the HDACs. In full agreement with the observation that HDAC3 overexpression represses the activity of the gdf11 promoter, depletion of HDAC3 but not HDAC1 or HDAC2 significantly increased the activity of the pGL191 promoter. These results strongly support the premise that HDAC3 represses transcription from the gdf11 promoter."

 

 

Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3.

Abstract

 

Fibroblast growth factor 21 (FGF21) stimulates fatty acid oxidation and ketone body production in animals. In this study, we investigated the role of FGF21 in the metabolic activity of sodium butyrate, a dietary histone deacetylase (HDAC) inhibitor. FGF21 expression was examined in serum and liver after injection of sodium butyrate into dietary obese C57BL/6J mice. The role of FGF21 was determined using antibody neutralization or knockout mice. FGF21 transcription was investigated in liver and HepG2 hepatocytes. Trichostatin A (TSA) was used in the control as an HDAC inhibitor. Butyrate was compared with bezafibrate and fenofibrate in the induction of FGF21 expression. Butyrate induced FGF21 in the serum, enhanced fatty acid oxidation in mice, and stimulated ketone body production in liver. The butyrate activity was significantly reduced by the FGF21 antibody or gene knockout. Butyrate induced FGF21 gene expression in liver and hepatocytes by inhibiting HDAC3, which suppresses peroxisome proliferator-activated receptor-α function. Butyrate enhanced bezafibrate activity in the induction of FGF21. TSA exhibited a similar set of activities to butyrate. FGF21 mediates the butyrate activity to increase fatty acid use and ketogenesis. Butyrate induces FGF21 transcription by inhibition of HDAC3.

 

There are different types of HDAC inhibitors, but lets find out what the down sides of specifically tributyrin and butyrate are -   Anyone know enough about sirtuins to interpret this?:

 

Differential regulation of the Sir2 histone deacetylase gene family by inhibitors of class I and II histone deacetylases.

Abstract  

The Sir2 histone deacetylase gene family consists of seven mammalian sirtuins (SIRTs) which are NAD-dependent histone/protein deacetylases. Sir2 proteins regulate, for instance, genome stability by chromatin silencing in yeast. In mammals, their function is still largely unknown. Due to the NAD+ dependency, Sir2 might be the link between metabolic activity and histone/protein acetylation. Regulation of gene expression also seems to play an important role in Sir2 functions, since increasing the dosage of Sir2 genes increases genome stability in yeast and Caenorhabditis elegans. We observed that the modification of histone/protein acetylation status by several class I and II histone deacetylase (HDAC) inhibitors induces differential changes in gene expression profiles of seven SIRT mRNAs in cultured neuronal cells. SIRT2, SIRT4 and SIRT7 were upregulated, whereas SIRT1, SIRT5 and SIRT6 were downregulated by trichostatin A (TSA) and n-butyrate. The upregulation of SIRT mRNAs was inhibited by actinomycin D. Interestingly, the regulation of SIRT mRNAs was highly similar both in mouse Neuro-2a neuroblastoma cells and post-mitotic rat primary hippocampal and cerebellar granule neurons. Using a chromatin immunoprecipitation technique, we showed that the upregulation of SIRT2 expression with TSA is related to the hyperacetylation of DNA-bound histone H4 within the first 500 bp upstream of the transcription start site of the SIRT2 gene. Chemically different types of HDAC inhibitors, such as TSA, apicidin, SAHA, M344 and n-butyrate induced remarkably similar responses in SIRT1-7 mRNA expression patterns. Differential responses in SIRT mRNA expression profiles indicate that the expression of the Sir2 family of genes is selectively regulated and dependent on histone/protein acetylation status.

 

Perhaps selective HDAC 3 inhibitors like this RGFP966 should be studied further? Here it was used to enhance the extinction of cocaine seekinng behavior: http://www.pnas.org/...364110.full.pdf

 

 


Edited by Phoenicis, 14 May 2014 - 04:24 PM.

  • Needs references x 1

#10 LexLux

  • Topic Starter
  • Guest
  • 265 posts
  • 88
  • Location:London, UK
  • NO

Posted 25 May 2014 - 09:35 PM

Are you sure this happens in non-cancer cells? For example compounds like Phyllanthus emblica will in fact only induce apoptosis in cancer cells.

Nice findings.

 

Is there any possibility to decrease the metabolism of Sodiumbutyrate ?

However, I´ve learned recently that Hdac inhibition can be even harmful

HDAC inhibitors: roles of DNA damage and repair.

http://www.ncbi.nlm....pubmed/23088869

 

Just Btw, if someone is interrested:

Effects of sodium butyrate on the expression of sodium channels by neuronal cell lines derived from the rat CNS

http://www.ncbi.nlm..../pubmed/1283997

 

 

I think our friend Phoenicis may have dropped a bombshell with this post though, it seems best results for cancer are obtained in combination with curcumin (iteself an HDACi) and similar epigenetic modulators. I read the Curcumin paper and found the DNA methylation topic especially intriguing - 

 

http://www.longecity...671&qpid=664507

 

 

Hiya!
 
I've been doing more research for an extended family member who also has NSCLC. If you find this interesting, get some independent medical advice on this, as always this is not intended to be medical advice. 
 
In short it seems that there is significant synergy between the epigenetic events regulated by HDACis like tributyrin and polyphenol compounds like curcumin (from turmeric) and ECGC (from green tea). The result is not only increased efficacy in the case of combination therapy, but also  a way to mitigate unwanted side effects from HDACi treatment alone. [1]
 
In the case of curcumin, this compound actually exhibits it's own HDACi effects and therefore appears to be a new member of the HDACi I class. [1] Here is what happens when it is combined with other HDACis - 
 
"When combined with HDAC inhibitors, curcumin not only suppresses HDACi activated tumor progression proteins and cell migration in vitro but also inhibited tumor growth and C metastasis invivo [81].Infact, preclinical animal studies, per- formed on xenograft mice injected with Hep3B hepatoma or H23 nonsmall cell lung cancer cells, revealed that HDACi treatment alone activated multiple protein kinase Cs and downstream substrates, enhancing tumor metastasis. Combined treatment of HDACi with protein kinase C inhibitors such as curcumin [82, 83] not only suppressed HDACi- activated proteins involved in tumor progression and cell migration in vitro (when used at a concentration of 50 M) but also inhibited tumor growth and metastasis in vivo (used at 40mg/kg/dose)[84].Combination of curcumin with HDACi drugs was thus suggested as an opportunity to develop low cost efficacy combination treatments for long-term cancer therapies in order to extend disease-free survival." [2]
 
NOTE - not sure how that in vivo dose translates into humans, a doctor could help you. You could ask him about figures calculated using a animal to human conversion; there was a thread covering that on this site too.
 
So even though different HDACis have been used in hundreds of clinical trials and yield promising results [3], suppression of protein kinase C by curcumin significantly improves the effectiveness  by mitigating the risk of activated proteins involved in tumor progression. ECGC should also suppress protein kinase C.  I really encourage you to read the recent review about curcumin - 'Curcumin as a Regulator of Epigenetic Events'.
 
In the case of ECGC, the polyphenol responsible for most of green tea's cancer fighting properties, it was found to be synergistic with the HDACi sodium butyrate (tributyrin is the prodrug). This seems to be primarily due to a a decrease in HDACi1, DNMT1, survivin and HDAC activity in general. The main benefit appears to be that one can combine low and physiologically achievable concentrations of ECGC and the HDACi for anti-cancer properties. The dosages they used were considered intermediate and achievable in vivo - 5mM for Sodium Butyrate and 10 micromolar for ECGC. [4] Consider reading the study on ECGC and Sodium Butyrate (referenced at [4]).
 
These are natural compounds which have a good safety profile when used in the correct dosages. Consult a physician for advice on dosing and also look at the clinical tirals that have been done on tributyrin as an indicator of safety. A quality curcumin supplement like theracurmin, which has been proven to have a high bio-availability, could possibly even be used in the recommended dosage found on the label. 
 
As for ECGC, there are studies that say using up to 700mg green tea extract daily is usually tolerable. Some people recommend splitting a 700mg dose into 2 x 350mg doses to avoid liver issues.  Supplements on the market tend to vary, some people here use LEF's green tea extract split in half, twice daily. Do further research to figure out how that translates into the mM concentration mention for ECGC above and see what the doctor says.
 
For sodium butyrate, the HDACi inhibitor mentioned earlier, it has a natural prodrug called tributyrin. Tributyrin is  more potent and bio-available than sodium butyrate. It overcomes "pharmacokinetic drawbacks of natural butyrate as a drug, i.e., its rapid metabolization and inability to achieve pharmacologic concentrations in neoplastic cells" [5] Unfortunately it may be a little harder to find, although it is cheap and is sold as a food flavouring. Sigma Aldrich is selling it in Germany and other suppliers carry it the USA. Sodium butyrate itself, is available as supplement on Amazon, but may not be the best option for the reason above. Vorinostat is a HDACi inhibiting anticancer drug often studied together with sodium butyrate, but would be expensive. 
 
Theracurmin  and green tea extracts are on amazon. 
 
 
[1] Curcumin as a regulator of epigenetic events, Marie-Hel´ene Teiten et al, Mol. Nutr. Food Res. 2013, 57, 1619–1629
[2] Ibid
[3]Therapeutic strategies to enhance the anticancer efficacy of histone deacetylase inhibitors. Miller CP et al
[4] Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate, Sabita N. Saldanha et al
[5]Tributyrin, a stable and rapidly absorbed prodrug of butyric acid, enhances antiproliferative effects of dihydroxycholecalciferol in human colon cancer cells. Gaschott T et al
 

 

 


Edited by LexLux, 25 May 2014 - 09:37 PM.


#11 LexLux

  • Topic Starter
  • Guest
  • 265 posts
  • 88
  • Location:London, UK
  • NO

Posted 25 May 2014 - 09:48 PM

The potential of HDAC inhibitors as cognitive enhancers.

 

www.ncbi.nlm.nih.gov/pubmed/23294310
by J Gräff - ‎2013

Annu Rev Pharmacol Toxicol. 2013;53:311-30. doi: 10.1146/annurev-pharmtox-011112-140216

 

Side Effects:

With respect to translational implications for the use of HDACis as cognitive treatments or enhancers, the route of administration becomes a key issue. Researchers are pursuing systemic methods of administration, but such methods might trigger side effects in nontargeted organs. Two studies reported neurotoxic effects upon HDACi treatment in animal models (91, 92). Strikingly, because these treatments were administrations of NaB and TSA, the neurotoxic effects might be due to the inhibition of the neuroprotective HDAC1. To our knowledge, no other reports of side effects in animal models exist. Given the extensive use of HDACis as potential cancer treatments, some side effects have also been reported in humans. These are dose-dependent and include thrombocytopenia, fatigue, confusion, hepatotoxicity, and abnormal electrocardiograph effects (70). In general, however, HDACis are well tolerated (60), which is surprising given that systemic routes of administration preclude tissue or even cell-type speci?city. This absence of drastic side effects in humans and animal models alike is even more surprising given the extensive cross talk of histone acetylation with other epigenetic modi?cations (93) and the resulting downstream consequences when only one epigenetic mark is affected. Because the brain performs a plethora of functions other than cognition, the notion of epigenetic cross talk is of particular importance in this organ. For instance, mood, anxiety, and depression also involve epigenetic modi?cations (35). In addition, chronically depressed patients as well as mice exposed to chronic social-defeat stress (a depression-like behavior-inducing paradigm in rodents) display reduced HDAC2 levels in the nucleus accumbens (94), a brain area involved in reward. Thus, reducing or inhibiting HDAC2 levels might not be desired in all brain areas. It would therefore be important to investigate histone acetylation (and other epigenetic modi?cations) in brain areas other than the ones involved in cognitive functions upon HDACi treatment aimed at memory enhancement. Doing so would help clarify whether a systemic administration results in systemic effects or only in effects in the targeted tissue. However, to our knowledge, such detailed studies are still lacking

 

[...]

 

CONCLUSIONS

 

In sum, HDACis have great potential as pharmacological treatments against neurological diseases characterized by memory impairments or as cognitive enhancers in the cognitively healthy. Their broad applicability and the remarkable absence of severe side effects strengthen this point. In contrast to the targeted therapeutic approaches aimed at enhancing cognition (111), HDACis represent a broader treatment at the level of chromatin, making it theoretically accessible to all genes implicated in learning and memory. Although alluring, such a nonspecific approach inherently harbors a greater potential for undesired side effects; therefore, any concerns about safety apply with even more vigor to HDACis. Nonetheless, HDACis might make it possible to reinstate some of brain cells? natural chromatin plasticity that is lost during development or disease via epigenetic modifications

 

http://www.ncbi.nlm....pubmed/23294310

 

Source cited in that review for neurotoxicity:

 

Inhibition of histone deacetylation enhances the neurotoxicity induced by the c-terminal fragments of amyloid precursor protein

 

  

The AICD (APP intracellular Domain) and C31, caspase-cleaved C-terminal fragment of APP, have been found in Alzheimer's disease (AD) patients' brains and have been reported to induce apoptosis in neuronal cells. In recent, the C-terminal fragments of amyloid precursor protein (APP-CTs) have been reported to form a complex with Fe65 and the histone acetyltransferase Tip60 and are thought to be involved in gene transcription. In this study, based on the hypothesis that APP-CTs might exert neurotoxicity by inducing some gene transcription, we investigated the effects of APP-CTs on histone acetylation which indicates that transcription is actively going on and also on the relationship between histone acetylation and the cytotoxicity induced by APP-CTs in nerve growth factor (NGF)-differentiated PC12 cells and rat primary cortical neurons. Here we demonstrate that the expression of APP-CTs [C31, AICD (C59) and C99] induces increases in acetylation of histone 3 and histone 4 and that treatment with sodium butyrate, an inhibitor of histone deacetylase, significantly enhances the cytotoxicity induced by APP-CTs. The acetylation of histone plays an important role in allowing regulatory proteins to access DNA and is likely to be a major factor in the regulation of gene transcription. Taken together, our results suggest that APP-CTs exert neurotoxicity by transcription-dependent mechanisms and this might contribute to the pathogenesis of AD. © 2003 Wiley-Liss, Inc

 

 

A free review that covers side effects:

 

HDAC inhibitors and neurodegeneration: at the edge between protection and damage

by KC Dietz - ‎2010


The use of histone deacetylase inhibitors (HDACIs) as a therapeutic tool for neurodegenerative disorders has been examined with great interest in the last decade. The functional response to treatment with broad-spectrum inhibitors however, has been heterogeneous: protective in some cases and detrimental in others. In this review we discuss potential underlying causes for these apparently contradictory results. Because HDACs are part of repressive complexes, the functional outcome has been characteristically attributed to enhanced gene expression due to increased acetylation of lysine residues on nucleosomal histones. However, it is important to take into consideration that the up-regulation of diverse sets of genes (i.e. pro-apoptotic and anti-apoptotic) may orchestrate different responses in diverse cell types. An alternative possibility is that broad-spectrum pharmacological inhibition may target nuclear or cytosolic HDAC isoforms, with distinct non-histone substrates (i.e. transcription factors; cytoskeletal proteins). Thus, for any given neurological disorder, it is important to take into account the effect of HDACIs on neuronal, glial and inflammatory cells and define the relative contribution of distinct HDAC isoforms to the pathological process. This review article addresses how opposing effects on distinct cell types may profoundly influence the overall therapeutic potential of HDAC inhibitors when investigating treatments for neurodegenerative disorders.

 

 


Edited by LexLux, 25 May 2014 - 09:53 PM.


#12 Flex

  • Guest
  • 1,629 posts
  • 149
  • Location:EU

Posted 26 May 2014 - 12:03 AM

Sry I´ve overead this about cancer cells.

I wonder whether Dnmt or Sirtuin have any effects for cognition or ageing.

 

Cocaine and Morphine do increase Sirt 1+2 and  Sirt1 respectively.

http://www.ncbi.nlm....pubmed/24107942

So as far as from what I understand, it decreases Synaptic plasticity

 

whereas it is on the other hand neuroprotective

http://www.ncbi.nlm....pubmed/22327552

 

 



#13 LexLux

  • Topic Starter
  • Guest
  • 265 posts
  • 88
  • Location:London, UK
  • NO

Posted 26 May 2014 - 12:18 AM

Im currently doing reading on the HDAC activities of the SIrt1, it seems like a double edged sword for cancer, but good for neuroprotection:

 

Sirtuin 1 (SIRT1) The Misunderstood HDAC

Walter Stünkel, Robert M. Campbell

3 2011 16: 1153 originally published online 15 November 2011J Biomol Screen 

 

"Diverse roles of sirt1 in biological pathways. sirt1 is a central regulator with impact on metabolic, neuronal, and immunological functions. sirt1 enhances insulin sensitivity, and aberrant function is associated with the etiology of type 2 diabetes mellitus. in addition, sirt1 has been shown to be neuroprotective and anti-inflammatory, both via deacetylation of nfκb. arrows with diamond-shaped ends show inhibitory action via deacetylation."
[...]
"sirt1’s dual roles in cancer. sirt1 functions as a context-dependent tumor suppressor and oncogene. sirt1 has direct repressive activity on a number of cancer-relevant pathways involving mtor, mutated brCa1, and aPC. however, in the context of mutations (e.g., negative regulators such as hiC1 and DbC1), sirt1 activity is enhanced, tipping the balance toward increased cancer cell survival, angiogen- esis, and cell cycle progression. arrows with diamond shaped ends show an inhiitory activity."
 

  • like x 1

#14 LexLux

  • Topic Starter
  • Guest
  • 265 posts
  • 88
  • Location:London, UK
  • NO

Posted 02 June 2014 - 08:43 PM

This is just my humble non-medical research, get independent medical advice if anything - 

 

Another HDAC inhibitor - beta-hydroxybutyrate, this recent publication has noted that the detrimental effects of HDAC1 inhibition are offset by SIRT1 activation (see pp.49 of the free full text). Similarly to trichostatin A, this HDACi actually also inhibits HDAC3, but it is less potent than butyrate. Tributyrin could be the among the most potent natural HDACis, but I'm not a doctor and cannot comment on it's safety. 

 

Could these then raise GDF-11? This may require further study.

 

Beta-hydroxybutyrate is actually a ketone and can be raised by calorie restriction, fasting, and by medium chain triglycerides. This ketone was traditionally thought of as an alternative source of energy for the brain when glucose levels are low, but has recently been found to act as a signalling molecule and an HDAC inhibitor.

 

A mere 30g/d of MCTs produces a mild ketosis, similar to calorie restriction, one could also reasonably expect similar effects. Aside from more energy and less appetite, these would be -

 

(Ref: John C. Newman, Ketone bodies as signaling metabolites, Trends Endocrinol Metab. 2014 Jan;25(1):42-52. [Be sure to see the full text])

  • lower mTOR activity
  • less IGF-1 signalling
  • more AMPK activity
  • Upregulation of FOXO3
  • more protein acetylation
  • more stress resistance

In Addition 

 


Edited by LexLux, 02 June 2014 - 09:06 PM.


#15 Ames

  • Guest
  • 361 posts
  • 74
  • Location:Cloud 7

Posted 01 August 2014 - 06:40 AM

I wonder if other CR mimics, such as NAG, have the same effect of raising beta-hydroxbutyrate.

 

So...has anyone tried supplementing with sodium butyrate? If so, can you recount your experience?

 

If not and there is a specific concern that is holding you back, can you list it for us?


Edited by golgi1, 01 August 2014 - 06:41 AM.


#16 Dan Raikov

  • Guest
  • 4 posts
  • 0

Posted 22 August 2014 - 07:15 PM

This here study says that HDAC provides brain protection by activating NRF2. It also inhibits the activity of keap, something that inhibits NRF2 activity.

 

http://ac.els-cdn.co...b34cbeb46a5c7d0

 

Also, I know that Ginkgo Biloba and Resveratrol and Turmeric have been said to activate NRF2 and inhibit keap.
 

E.g. Ginkgo Biloba:

 

http://www.sciencedi...24320507000975#


Edited by Dan Raikov, 22 August 2014 - 07:22 PM.


#17 Flex

  • Guest
  • 1,629 posts
  • 149
  • Location:EU

Posted 18 February 2015 - 12:44 PM

This here study says that HDAC provides brain protection by activating NRF2. It also inhibits the activity of keap, something that inhibits NRF2 activity.

 

http://ac.els-cdn.co...b34cbeb46a5c7d0

 

Also, I know that Ginkgo Biloba and Resveratrol and Turmeric have been said to activate NRF2 and inhibit keap.
 

E.g. Ginkgo Biloba:

 

http://www.sciencedi...24320507000975#

 

Gastrodia ellata aka Tian Ma

does also activate NRF2 (tough its expensive) as well as some others:

http://www.longecity...gh/#entry713700

 

Try to recherche: NRF2+ Herb + compound in ncbi or in google hinwai.com + NRF2 or google scholar



sponsored ad

  • Advert
Click HERE to rent this advertising spot for BRAIN HEALTH to support LongeCity (this will replace the google ad above).

#18 Flex

  • Guest
  • 1,629 posts
  • 149
  • Location:EU

Posted 18 February 2015 - 12:51 PM

 

Im currently doing reading on the HDAC activities of the SIrt1, it seems like a double edged sword for cancer, but good for neuroprotection:

 

Sirtuin 1 (SIRT1) The Misunderstood HDAC

Walter Stünkel, Robert M. Campbell

3 2011 16: 1153 originally published online 15 November 2011J Biomol Screen 

 

"Diverse roles of sirt1 in biological pathways. sirt1 is a central regulator with impact on metabolic, neuronal, and immunological functions. sirt1 enhances insulin sensitivity, and aberrant function is associated with the etiology of type 2 diabetes mellitus. in addition, sirt1 has been shown to be neuroprotective and anti-inflammatory, both via deacetylation of nfκb. arrows with diamond-shaped ends show inhibitory action via deacetylation."
[...]
"sirt1’s dual roles in cancer. sirt1 functions as a context-dependent tumor suppressor and oncogene. sirt1 has direct repressive activity on a number of cancer-relevant pathways involving mtor, mutated brCa1, and aPC. however, in the context of mutations (e.g., negative regulators such as hiC1 and DbC1), sirt1 activity is enhanced, tipping the balance toward increased cancer cell survival, angiogen- esis, and cell cycle progression. arrows with diamond shaped ends show an inhiitory activity."
 

 

 

Afaik Nicotineamide is a SIRT 1&2 activator (in low doses) and inhibitor in high doses.







Also tagged with one or more of these keywords: gdf-11, brain, function

0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users